The Inflammatory Response (Inflammation)
Inflammation is an essential localized host response to invading microorganisms or tissue injury which involves cells of the immune system. The classic signs of inflammation include redness (erythema), swelling (edema), pain and increased heat production (pyrema) at the site of injury. The inflammatory response allows the body to specifically recognize and eliminate an invading organism and/or repair tissue injury. Many of the acute changes at the site of inflammation are either directly or indirectly attributable to the massive influx of leukocytes (e.g., neutrophils, eosinophils, lymphocytes, monocytes) which is intrinsic to this response. Leukocytic infiltration and accumulation in tissue results in their activation and subsequent release of inflammatory mediators such as LTB4, prostaglandins, TNF-α, IL-1β, IL-8, IL-5, IL-4, histamine, proteases and reactive oxygen species for example.
Normal inflammation is a highly regulated process that is tightly controlled at several levels for each of the cell types involved in the response. For example, expression of the pro-inflammatory cytokine TNF-α is controlled at the level of gene expression, translation, post-translational modification and release of the mature form from the cell membrane. Many of the proteins up-regulated during inflammation are controlled by the transcription factor, NF-κB. Pro-inflammatory responses are countered in some instances by endogenous anti-inflammatory mechanisms such as generation of IL-10. A characteristic of a normal inflammatory response is that it is temporary in nature and is followed by a resolution phase which brings the state of the tissue back to its prior condition. The resolution phase is thought to involve up-regulation of anti-inflammatory mechanisms, such as IL-10, as well as down-regulation of the pro-inflammatory processes.
Inflammatory Disease
Inflammatory disease occurs when an inflammatory response is initiated that is inappropriate and/or does not resolve in the normal manner but rather persists and results in a chronic inflammatory state. Inflammatory disease may be systemic (e.g., lupus) or localized to particular tissues or organs and exerts an enormous personal and economic burden on society. Examples of some of the most common and problematic inflammatory diseases include asthma, allergy, rheumatoid arthritis, inflammatory bowel disease, psoriasis, emphysema, colitis, graft vs host disease, contact dermatitis, and ischemia-reperfusion injury. Other disease states such as immunodeficiency diseases are now known to be associated with altered regulation of the chemokine/cytokine network and their receptors, which can alter viral replication and AIDS pathogenesis.
Many of the tissue, cellular and biochemical processes which are perturbed in inflammatory disease have been elucidated and this has allowed the development of experimental models or assays to mimic the disease state. These in-vitro and in-vivo assays enable selection and screening of compounds with a high probability of therapeutic efficacy in the relevant inflammatory disease. For example, the ability of a compound to inhibit the allergen-induced accumulation of inflammatory cells such as eosinophils and lymphocytes in the lavage fluid obtained from sensitized animals is indicative of anti-asthma activity. In particular, this model system is useful in the evaluation of the effects of compounds in the treatment of the late phase response and hyper-responsiveness that is characteristic of asthma, when lung inflammation is apparent.
Asthma and Allergy
Asthma and allergy are closely related with good evidence from clinical studies demonstrating a strong correlation between the severity of asthma and the degree of atopy (allergy). Sensitization to allergens is believed to be the most important risk factor for asthma in both children and adults, with approximately 90% of asthma cases exhibiting atopy.
Allergy is characterized by an increased blood serum IgE (antibody) level. Repeated exposure to allergens, in a process called sensitization, is normally required to trigger atopy and the subsequent asthmatic or allergic response. Once B cells are exposed to allergens, they produce antibodies which bind to the surface of mast cells. The crosslinking of two antibodies by the antigen causes a series of reactions resulting in degranulation and the release of a number of mediators which modulate the inflammatory response. Mediators that are released or generated during the asthmatic and allergic response include histamine, leukotrienes, prostaglandins, cytokines and tryptase.
Asthma is characterized by hyperresponsiveness of the airways, episodic periods of bronchospasm and chronic inflammation of the lungs. Obstruction of the airways is reversible with time or in response to drug therapies. Patients exhibiting normal airflow may be hyperreactive to a variety of naturally occurring stimuli, e.g., cold air, exercise, chemicals and allergen. The most common event initiating an asthmatic response is an immediate hypersensitivity to common allergens including ragweed pollen, grass pollen, various fungi, dust mites, cockroaches and domestic animals. The symptoms of the disease include chest tightness, wheezing, shortness of breath and coughing. Asthma incidence and mortality has been increasing worldwide, doubling over the past 20 years despite modern therapies.
The responses of the airways to allergen is complex and consists of an early asthmatic response (EAR) which peaks 20–30 min after exposure to the stimuli, is characterized by bronchoconstriction and normally resolves after 1½ to 2 hours. The late asthmatic response (LAR) generally occurs 3–8 hours after initial exposure, and involves both bronchoconstriction and the development of inflammation and edema in the lung tissue. This inflammation often becomes chronic, with epithelial damage occurring and infiltration of the lungs with inflammatory cells such as eosinophils and neutrophils.
Current Treatments for Asthma
Glucocorticoids (steroids) are the most effective long-term therapy for the treatment of asthma. For example, due to the presence of airway inflammation even in mild asthma, inhaled steroids are used even in early stage drug therapy. Although steroids are effective anti-inflammatories they are not very useful for the control of acute asthma attacks. Orally delivered steroids are associated with significant side-effects and consequently their chronic use in the control of asthma is minimal. Combination therapy is often employed for orally delivered steroids, where combination therapy may be divided into the following areas: anti-inflammatory drugs (e.g., inhaled and oral steroids), bronchodilators, (e.g., β2-agonists, xanthines, anticholinergics), and mediator inhibitors (e.g., cromolyns and leukotriene antagonists). In general, moderate to severe asthma patients are poorly served by the present armamentarium of drugs. Drugs that are safe are only marginally effective, while effective drugs have unacceptable side effects with extensive monitoring of patients required. Products under development continue to meet challenges related to side-effects (e.g., emesis side-effects characteristic of certain phosphodiesterase 4 inhibitors) and poor pharmacokinetic and metabolism parameters. There is a significant need for therapeutic agents that achieve safe and effective treatment of inflammatory diseases such as asthma and allergy. The present invention provides these and related benefits as described herein.